Is MIDEAS p.Pro755Ser (c.2263C>T) pathogenic?

MIDEAS p.Pro755Ser (c.2263C>T) is classified Uncertain significance in MIDEAS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-25). AlphaMissense: likely pathogenic (0.8585); Very rare (popmax 0.0011%, nfe).

How common is MIDEAS p.Pro755Ser (c.2263C>T) in the general population?

MIDEAS p.Pro755Ser (c.2263C>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about MIDEAS p.Pro755Ser (c.2263C>T)?

AlphaMissense predicts likely pathogenic (score 0.8585) — an in-silico prediction, not a clinical call.

MIDEAS p.Pro755Ser

c.2263C>T · rs2503082569 · VCV3126365

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8585 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8585	likely pathogenic
REVEL	0.602	indeterminate
SaProt	LLR -11.77	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 11 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,178,872 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000868% 14/1,612,646 alleles · very rare exomes 14/1,460,272 · genomes 0/152,374 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,394
European (non-Finnish)grpmax	0.0011%	90,682

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MIDEAS
Protein: p.Pro755Ser
Coding: c.2263C>T
MANE Select: NM_001367710
dbSNP: rs2503082569
Type: single nucleotide variant
Location: chr14:73726872 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 48.77 · 3 PDB
Residue 755: the elm2 domain

Full MIDEAS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MIDEAS c.2162+1G>A Uncertain significance ★ same type
MIDEAS p.Ala1001Val Uncertain significance ★ ⚠ same type
MIDEAS p.Ala170Val Uncertain significance ★ ⚠ same type
MIDEAS p.Ala203Thr Uncertain significance ★ ⚠ same type
MIDEAS p.Ala324Asp Uncertain significance ★ ⚠ same type
MIDEAS p.Ala55Glu Uncertain significance ★ ⚠ same type
MIDEAS p.Ala55Thr Uncertain significance ★ ⚠ same type
MIDEAS p.Ala620Thr Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mideas-p-pro755ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown